CHEMOTATIC MECHANISMS IN NEONATAL BACTERIAL INFECTION

新生儿特别容易受到细菌感染。 因为宿主防御不成熟。最一致的缺陷之一是 新生儿的宿主防御系统是一个明显的异常 多形核白细胞趋化性。不幸的是，几乎没有 已知这种细胞发育缺陷的发病机制 有动静。在这笔赠款的头两年进行的研究中， 我们发现新生儿的PMN不能形成聚合体或F。 肌动蛋白，在化学诱导剂刺激后由凝胶肌动蛋白转化而来的；一个过程 这在提供细胞所需的收缩力量方面是必不可少的 有动静。更多的实验表明，新生儿的中性粒细胞无法 在化疗后经历膜电位的严重变化 因子刺激和发展较低浓度的细胞内游离 钙。早期环腺苷3‘5’一磷酸(CAMP)对 趋化因子的刺激在新生儿的PMN中也是钝化的。 这些结果表明可能导致信号转导的异常。 在人类中观察到的细胞运动的发育异常 刚出生的。基于这些相当令人振奋的初步结果，我们希望 试图定义缺陷的确切机制(S)，并试图 纠正异常情况。具体地说，我们将1)确定刚性的 新生儿中性粒细胞的细胞膜阻止侧向运动 受体和钝化或阻断信号转导；2)试图 定义缺乏变化的原因和意义 膜电位和细胞内游离的较小幅度的增加 新生儿中性粒细胞中的细胞内钙；以及3)试图发展 纠正阿司匹林趋化反应性的药物方案 新生儿中性粒细胞。

The newborn human infant is especially susceptible to bacterial infections because of immature host defenses. One of the most consistent defects in the neonate's host defense system is a marked abnormality in polymorphonuclear leukocyte chemotaxis. Unfortunately, very little is known about the pathogenesis of this developmental defect in cell movement. In studies carried out during the first two years of this grant, we have shown that the PMNs from neonates fail to form polymerized, or F actin, from gel actin following stimulation with chemoattractant; a process which is essential in providing the contractile forces required for cell movement. Additional experiments indicate that the PMNs from neonates fail to undergo critical changes in membrane potential following chemotactic factor stimulation and develop lower concentrations of intracellular free calcium. The early cyclic adenosine 3'5' monophosphate (cAMP) response to chemotactic factor stimulation is also blunted in the PMNs from neonates. These results suggest that an abnormality in signal transduction may result in the developmental abnormality in cell motility observed in the human neonate. Based on these rather exciting preliminary results, we wish to attempt to define the exact mechanism(s) of the defect and attempt to correct the abnormality. Specifically, we will 1) determine if the rigid cell membrane of the PMNs from neonates is preventing lateral mobility of receptors and blunting or blocking signal transduction; 2) attempt to define the reasons for, and significance of, the lack of changes in membrane potential and the smaller increases in intracellular in free intracellular calcium in the neonatal PMN; and 3) attempt to develop pharmacologic regimens for correcting the chemotactic responsiveness of PMNs from neonates.